The invention relates to inhibitors of kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which kinases may be involved, symptoms of such disease, or the effect of other physiological events mediated by kinases. The invention also provides for methods of making kinase inhibitor compounds and methods for treating diseases in which kinase activity is involved.
The protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton et al., Science, 253:407-414 (1991); Hiles et al., Cell, 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993); Garcia-Bustos et al., EMBO J., 13:2352-2361 (1994)).
Since the structure of the catalytic subunit of cAMP-dependent protein kinase (cAPK) was elucidated, approximately two dozen additional kinase structures have been solved as either apo enzymes or binary and ternary complexes (with ATP, ATP analogs, metal ions, ADP, ATP competitive inhibitors in the absence or presence of peptide substrate or peptide inhibitors). These proteins share a structurally conserved catalytic domain comprising two lobes that can be further subdivided into twelve subdomains. The N-terminal portion forms the small lobe (including subdomains I-IV) whose architecture is composed of an antiparallel five-strand xcex2-sheet and one xcex1-helix, while the lower C-terminal domain forms another lobe (including subdomains VIA-XI) containing mostly xcex1-helical architecture. Subdomain V spans the two lobes. The N-terminal domain is thought to participate in orienting the nucleotide (or other binding entity), while the C-terminal domain is thought to be responsible for binding peptide substrate and initiating phosphotransfer to the hydroxyl group of a serine, threonine, or tyrosine residue.
The N- and C-terminal domains are connected through a single peptide strand, to which the adenine moiety of ATP binds via an eleven membered hydrogen bond cycle, involving the N1 and the N6 amino group, and the backbone carbonyl and NH functions of two nonconsecutive residues. This linker acts as a hinge about which the domains can rotate with respect to each other without disruption of the secondary architecture of the kinase. Several torsion angle changes in the linker backbone allow this movement to occur. The ribose group of ATP is anchored to the enzyme via hydrogen bonds with residues within the ribose-binding pocket. The triphosphate group is held in position via various polar interactions with several variable residues form the glycine rich loop, the conserved DFG motive and the catalytic loop.
Protein kinases may be characterized by their regulation mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions.
Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of proto-oncogene encoded protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including cancer and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
The invention relates to compounds of the formula: 
wherein,
R1 is H; CN; COOR5; C(O)NR5R5; halo; C1-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with 1-3 independent NR5R5, NR5R6, SR5 or OR5; or C1-C10 alkenyl substituted with 1-3 independent NR5R5, NR5R6, SR5 or OR5;
R2 is NR5R5; SR5; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R15; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with 1-3 independent aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with 1-3 independent aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
R3 is phenyl substituted with 1-3 independent R4; R8; COOR5; or C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8;
X is O or S; and
the remaining groups are as defined herein.
The invention also relates to compositions comprising these compounds, methods of making these compounds, methods of inhibiting enzyme activity, particularly kinase activity, through use of these compounds, and methods of treating disease or disease symptoms in a mammal, particularly where modulation of enzyme activity, and more particularly kinase activity, can affect disease outcome.
The invention provides compounds useful in inhibiting kinase activity and inhibiting kinases or other polypeptides having sequences or subsequences homologous to kinase sequences or subsequences. In one embodiment, the inhibitory compound has the formula: 
wherein,
R1 is H; CN; COOR5; C(O)NR5R5; halo; C1-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with 1-3 independent NR5R5, NR5R6, SR5 or OR5; or C1-C10 alkenyl substituted with 1-3 independent NR5R5, NR5R6, SR5 or OR5 ;
R2 is NR5R5; SR5; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R15; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with 1-3 independent aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with 1-3 independent aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
R3 is phenyl substituted with 1-3 independent R4; R8; COOR5; or C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8;
X is O or S; and
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with 1-3 independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with 1-3 independent aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2 R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with 1-3 independent R7, R9 or aryl; or C1-C10 alkenyl substituted with 1-3 independent R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with 1-3 independent aryl, R7 or R9;
Each R16 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R9 groups; C1-C10 alkenyl substituted with 1-3 independent aryl, R7 or R9; or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12; NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; and
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12.
Preferred compounds include those of the formula above wherein X is O.
In another embodiment, the compounds of the formula above are those wherein,
R1 is H; COOR5; C(O)NR5R5; halo; C2-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with NR5R5, NR5R6, SR5 or OR5; or C1-C10 alkenyl substituted with NR5R5, NR5R6, SR5 or OR5;
R2 is NR5R15; SR5; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R16; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
R3 is phenyl substituted with 1-3 independent R4; R8; COOR5; or C1-C10 alkyl substituted with aryl, R7 or R8;
X is O or S;
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R16 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C1-C10 alkenyl substituted with aryl, R7 or R9; or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C10 alkyl substituted with R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12. Preferred compounds of this embodiment are also those wherein X is O.
In another embodiment, the invention relates to a compound of the formula, 
wherein,
R1 is CN;
R2 is NR5R15; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5 ; NR5xe2x80x94R16; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
X is O or S;
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R14 is each independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R16 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C1-C10 alkenyl substituted with aryl, R7 or R9; or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C10 alkyl substituted with R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12;
Each R17 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12 R12, OC(O)R12; or R12;
wherein when all R4 and R17 are simultaneously H, R14 may not be Me, Cl, OMe or NO2; and wherein R14 and R17 may not simultaneously be Cl. Preferred compounds of this embodiment are also those wherein X is O. Alternatively, the compound has the formula directly above wherein each R14 is independently selected from C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; I; Br; F; CF3; SR5; OR25; NR5R5; NR5R6; COOR5; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8; and each R25 is independently H; C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;. Alternatively, the compound has the formula directly above wherein each R14 is independently selected from NR5R5; NR5R6; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; or NR5C(O)C(O)NR5R6. In alternate embodiments, the compound is of any of the formulae above, wherein at least two of R4 and/or R17 are independently H. Preferred compounds of these embodiments are also those wherein X is O.
In an alternate embodiment, the inhibitory compound has the formula: 
wherein,
R1 is CN;
R2 is NR5R15; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R16; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
X is O or S;
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2 R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R14 is independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R16 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C1-C10 alkenyl substituted with aryl, R7 or R9; or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C10 alkyl substituted with R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12;
wherein when all R4 are H, R14 may not be Me or OMe. Preferred compounds of this embodiment are also those wherein X is O. Alternatively, the compound has the formula directly above wherein each R14 is independently selected from C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; CF3; SR5; OR25; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8; and each R25 is independently H; C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9. Alternatively, the compound has the formula directly above wherein each R14 is independently selected from NR5R5; NR5R6; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; or NR5C(O)C(O)NR5R6. In alternate embodiments, the compound is of any of the formulae above, wherein at least two of the R4 are independently H. Preferred compounds of these embodiments are also those wherein X is O.
In an alternate embodiment, the inhibitory compound has the formula, 
wherein,
R1 is CN;
R2 is NR5R15; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R16; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
X is O or S;
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-Cor cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R14 is independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R5; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R16 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R17 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R12; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12;
wherein R14 and R17 may not simultaneously be Cl and wherein R14 may not simultaneously be methyl when all R4 and R17 are H. Preferred compounds of this embodiment are also those wherein X is O. Alternatively, the compound has the formula directly above wherein each R17 is independently selected from from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; I; Br; F; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8. Alternatively, the compound has the formula directly above wherein each R14 is independently selected from NR5R5; NR5R6; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; or NR5C(O)C(O)NR5R6. In alternate embodiments, the compound is of any of the formulae above, wherein at least two of R4 and/or R17 are independently H. Preferred compounds of these embodiments are also those wherein X is O.
In another embodiment, the inhibitory compound has the formula, 
wherein,
R1 is CN;
R2 is NR5R15; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R16; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
R3 is R8; COOR5; or C1-C10 alkyl substituted with R7, R8, or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C10 alkyl substituted with R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; wherein R3 is not unsubstituted furanyl, unsubstituted thienyl or unsubstituted pyridyl;
X is O or S;
Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13,or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R15 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R16 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C1-C10 alkenyl substituted with aryl, R7 or R9; or phenyl substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12, C1-C1 alkyl substituted with R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12;
Each R19 is independently H; C1-C1 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12. Alternatively, the compound has the formula directly above wherein each R3 is R8, and alternatively, wherein R3 is R8 that is attached by a nitrogen atom in the R8 ring system. Preferred compounds of these embodiments are also those wherein X is O.
In another embodiment, the inhibitory compound has the formula, 
wherein,
R2 is NR5R5; SR5; OR5; R8; aryl; N(R5)xe2x80x94Nxe2x95x90CH(R8); N(R5)xe2x80x94Nxe2x95x90CH(aryl); NR5xe2x80x94NR5C(O)NR5R5; NR5xe2x80x94NR5R15; NR5xe2x80x94NR5R6; C1-C10 alkyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5; or C1-C10 alkenyl substituted with aryl, R8, halo, CF3, SR5, OR5, OC(O)R5, NR5R5, NR5R6, COOR5, NO2, CN, C(O)R5, C(O)NR5R5, or S(O)2NR5R5;
X is O or S;
R4 is one, two, or three substituents, each independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; NR5R5; NR5R6; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; OC(O)R5; S(O)2R5; S(O)2NR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)2NR5R5; NR5S(O)2R5; NR5S(O)2R8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with aryl, R7 or R8; or C1-C10 alkenyl substituted with aryl, R7 or R8;
Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-C10 alkyl substituted with one or two independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R7 or R9 groups; or C1-C10 alkenyl substituted with aryl, R7 or R9;
Each R6 is independently C(O)R5, COOR5, or S(O)2R5;
Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11 , NR11R11, COOR10, NO2, CN, C(O)R10, or C(O)NR10R10;
Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; haloalkyl; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; C1-C10 alkyl substituted with R7, R9 or aryl; C1-C10 alkenyl substituted with R7, R9 or aryl;
Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10R10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; or C(O)NR10R10;
Each R10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R11 is independently C(O)R10, COOR10, or S(O)2R10;
Each R12 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NHC(O)R13, or OC(O)R13;
Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN; or phenyl optionally substituted with halo, CF3, OR19, SR19, NR19R19, COOR19, NO2, CN;
Each R18 is independently C1-C10 alkyl or both R18 may be taken together as a C2-C7 alkyl chain; wherein any R18 may optionally be substituted with 1-3 independent R7 or R8;
Each R19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;
Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12. Preferred compounds of this embodiment are also those wherein X is O.
Alternate embodiments of the invention are those of any of the formulae described herein wherein R2 is NR15R5; wherein R2 is NHR15; and wherein R2 is NR5R15 and said R15 is independently phenyl substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR12; SR12; NR12R12; COOR12; NO2; CN; C(O)R12; C(O)C(O)R12; C(O)NR12R12; S(O)2R12; N(R12)C(O)R12; N(R12)(COOR12); N(R12)S(O)2R12; S(O)2NR12R12; OC(O)R12; NR12C(O)NR12R12; NR12C(O)C(O)R12; NR12C(O)R9; NR12S(O)2NR12R12; NR12S(O)2R9; NR12C(O)C(O)NR12R12; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NHC(O)R12, NH(COOR12), S(O)2NR12R12, OC(O)R12; or R12.
The invention also relates to methods of inhibiting enzyme or polypeptide activity, particularly of an enzyme or polypeptide described herein, such as a kinase, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. In one embodiment, the invention relates to a method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any one of the formulae described herein. Preferably, the mammal is a human.
In another embodiment, the invention relates to a method of inhibiting enzyme activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.
The invention also relates to methods of treating disease and/or disease symptoms, particularly those mediated by an enzyme or polypeptide described herein, such as kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. Such diseases or disease symptoms are described herein. xe2x80x9cKinase mediatedxe2x80x9d disease or disease symptoms refers to disease or disease symptoms in which kinase activity is involved. In one embodiment, this invention relates to a method of treating disease or disease symptoms, particularly kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.
In an alternate embodiment, this invention relates to a method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.
In the compounds described herein, the term xe2x80x9chaloxe2x80x9d refers to any radical of fluorine, chlorine, bromine or iodine. The terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to hydrocarbon chains that may be straight-chain or branched-chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates the group may have from 1 to 10 (inclusive) carbon atoms in it. The terms xe2x80x9cringxe2x80x9d and xe2x80x9cring systemxe2x80x9d refer to a ring comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed.
In the methods described herein, said mammal is preferably a human. The inhibitors described herein, however, are useful in inhibiting kinase activity in human cells and useful in murine and other species used as surrogates for investigating activity in vitro and in vivo in humans and against human kinases. The inhibitors described herein are also useful for investigating inhibition and activity of kinases originating from species other than humans.
The compounds and compositions described herein are useful for inhibition of kinase activity of one or more enzymes. Kinases include, for example, protein kinases, lipid kinases (e.g., phosphatidylinositol kinases PI-3, PI-4) and carbohydrate kinases. Further information relating to kinase structure, function and and their role in disease or disease symptoms is available at the Protein Kinase Resource web site (http://www.sdsc.edu/Kinases/pk_home.html). Kinases may be of prokaryotic, eukaryotic, bacterial, viral, fungal or archaea origin. Specifically, the compounds described herein are useful as inhibitors of tyrosine, serine/threonine or histidine protein kinases. Examples of kinases that are inhibited by the compounds and compositions described herein and against which the methods described herein are useful include, but are not limited to, LCK, IRK (=INSR=Insulin receptor), IGF-1 receptor, SYK, ZAP-70, IRAK1, IRAK2, BLK, BMX, BTK, FRK, FGR, FYN, HCK, ITK, LYN, TEC, TXK, YES, ABL, SRC, EGF-R (=ErbB-1), ErbB-2 (=NEU=HER2), ErbB-3, ErbB-4, FAK, FGF1R (=FGR-1), FGF2R (=FGR-2), IKK-1 (=IKK-ALPHA=CHUK), IKK-2 (=IKK-BETA), MET (=c-MET), NIK, PDGF receptor ALPHA, PDGF receptor BETA, TIE1, TIE2 (=TEK), VEGFR1 (=FLT-1), VEGFR2 (=KDR), FLT-3, FLT4, KIT, CSK, JAK1, JAK2, JAK3, TYK2, RIP, RIP-2, LOK, TAK1, RET, ALK, MLK3, COT, TRKA, PYK2, EPHB4, RON, GSK3, UL13, ORF47, ATM, CDK (including all subtypes), PKA, PKB (including all PKB subtypes) (=AKT-1, AKT-2, AKT-3), PKC (including all PKC subtypes), and bARK1 (=GRK2) (and other G-protein coupled receptor kinases (GRKs)), and all subtypes of these kinases. The compounds and compositions of the invention are therefore also particularly suited for treatment of diseases and disease symptoms that involve one or more of the aforementioned protein kinases. In one embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by LCK, ZAP, LYN, EGFR, ERB-B2, KDR, ITK, BTK, or SYK. In another embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by src-family kinases. In another embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by kinases in one of the kinase families defined by Hardie and Hanks, ed. supra. The compounds and compositions are also suited for regulating or modulating signal transduction in signal transduction pathways that involve one or more kinases, thus affecting events in a cell, and are therefor useful in methods for regulating or modulating signal transduction.
The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase sequence, including the kinases mentioned herein. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising a subsequence, or variant thereof, of any enzyme that comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase subsequence, including subsequences of the kinases mentioned herein. Such subsequence preferably comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with the sequence of an active site or subdomain of a kinase enzyme. The subsequences, or variants thereof, comprise at least about 300, or alternatively at least about 200, amino acids.
The inhibitors described herein are useful for inhibiting the biological activity of any enzyme that binds ATP and thus for treating disease or disease symptoms mediated by any enzyme that binds ATP. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme that is involved in phosphotransfer and thus for treating disease or disease symptoms mediated by any enzyme that is involved in phosphotransfer. The inhibitors described herein are also useful for inhibiting the biological activity of a polypeptide or enzyme having sequence homology with a kinase sequence and thus for treating disease or disease symptoms mediated by such polypeptide or enzyme. Such polypeptides or enzymes may be identified by comparison of their sequence with kinase sequences and kinase catalytic domain sequences. For example, one method of comparison involves the database PROSITE (http://expasy.hcuge.ch), containing xe2x80x9csignaturesxe2x80x9d or sequence patterns (or motifs) or profiles of protein families or domains. Thus, the inhibitors described herein are useful for inhibiting the biological activity of a polypeptide or enzyme comprising a sequence that comprises a xe2x80x9csignaturexe2x80x9d or sequence pattern or profile derived for, and identified in PROSITE as relating to kinases, and for treating disease or disease symptoms mediated by such polypeptide or enzyme. Examples of such PROSITE motifs or consensus patterns identified as relating to kinases include PS00107, PS00108, PS00109, PS50011, PS00915, and PS00916.
The compounds, compositions and methods described herein are useful in inhibiting kinase activity. As such, the compounds, compositions and methods of this invention are useful in treating kinase-mediated disease or disease symptoms in a mammal, particularly a human. Kinase mediated diseases are those wherein a protein kinase is involved in signaling, mediation, modulation, or regulation of the disease process. Kinase mediated diseases are exemplified by the following disease classes: cancer, autoimmunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, angiogenesis, neovascularization, vasculogenesis, cardiovascular, and the like.
The compounds, compositions and methods described herein are useful in treating or preventing diseases or their symptoms, including, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts), graft versus host disease, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes, diabetic retinopathy, asthma, inflammatory bowel disease (Crohn""s disease, ulcerative colitis), renal disease, cachexia, septic shock, lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, Alzheimer""s disease, Parkinson""s disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo purging for autologous or allogeneic bone marrow transplantation, leukemia (acute myeloid, chronic myeloid, acute lymphoblastic, etc.), cancer (breast, lung, colorectal, ovary, prostate, renal, squamous cell, prostate, glioblastoma, melanoma, pancreatic, Kaposi""s sarcoma, etc.), occular disease, retinopathies, (e.g., macular degeneration, diabetic retinopathy), corneal disease, glaucoma, bacterial infections, viral infections, fungal infections and heart disease, including but not limited to, restenosis. In one embodiment, the compositions and methods described herein are useful in treating or preventing rheumatoid arthritis, transplant rejection, asthma or allergy, or their symptoms.
Another embodiment envisioned by this invention relates to the use of the kinase inhibitory compounds described herein for use as reagents that effectively bind to kinases. As reagents, the compounds of this invention, and their derivatives, may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. The compounds of this invention, and their derivatives, may also be modified (e.g., radiolabelled or affinity labelled, etc.) in order to utilize them in the investigation of enzyme or polypeptide characterization, structure, and/or function. These and other uses that characterize kinase inhibitors will be evident to those of ordinary skill in the art.
In another embodiment, the inhibitors described herein are useful for crystallizing or co-crystallizing with a protein kinase. Such crystals or crystal complexes may additionally comprise additional peptides and or metal ions. The crystals or crystal complexes may be used for investigation and determination of enzyme characteristics including, for example, structure of the kinase enzyme, enzyme active site domains, and inhibitor-enzyme interactions. This information is useful in developing inhibitor compounds with modified characteristics and for understanding structure-function relationships of the enzymes and their enzyme-inhibitor interactions.
In an alternate embodiment, the inhibitory compounds described herein may be used as platforms or scaffolds which may be utilized in combinatorial chemistry techniques for preparation of derivatives and/or chemical libraries of compounds. Such derivatives and libraries of compounds have kinase inhibitory activity and are useful for identifying and designing compounds possessing kinase inhibitory activity. Combinatorial techniques suitable for utilizing the compounds described herein are known in the art as exemplified by Obrecht, D. and Villalgrodo, J. M., Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998), and include those such as the xe2x80x9csplit and poolxe2x80x9d or xe2x80x9cparallelxe2x80x9d synthesis techniques, solid-phase and solution-phase techniques, and encoding techniques (see, for example, Czarnik, A. W., Curr. Opin. Chem. Bio., (1997) 1, 60. Thus, one embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing a body comprising a plurality of wells; 2) providing one or more compounds of the formulae described herein in each well; 3) providing an additional one or more chemicals in each well; 4) isolating the resulting one or more products from each well. An alternate embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing one or more compounds of the formulae described herein attached to a solid support; 2) treating the one or more compounds of the formulae described herein attached to a solid support with one or more additional chemicals; 3) isolating the resulting one or more products from the solid support. In the methods described above, xe2x80x9ctagsxe2x80x9d or identifier or labeling moieties may be attached to and/or detached from the compounds of the formulae herein or their derivatives, to facilitate tracking, identification or isolation of the desired products or their intermediates. Such moieties are known in the art. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. Examples of such chemicals are those that appear in the various synthetic and protecting group chemistry texts and treatises referenced herein.
The compounds of the formulae herein may be used to study the mechanism and role of enzymes in biological pathways and processes involving kinases. The compounds of the formulae herein may also be used as probes to identify new kinase enzymes or polypeptides with sequence homology to kinases. The inhibitor compounds may be tethered to a support or modified (e.g., tagged, radiolabeled or other identifiable detection method) such that the compound may be detected and isolated in the presence of the kinase enzyme or polypeptide. Thus, another embodiment relates to a method of identifying and/or isolating a kinase enzyme or polypeptide with sequence homology to a kinase enzyme sequence or subsequence, comprising, contacting a tethered or modified compound of any of the formulae herein with one or more polypeptides, isolating a polypeptide/inhibitor complex, and identifying or isolating the sequence of the polypeptide in the polypeptide/inhibitor complex. The identification of the polypeptide sequence may be performed while in the polypeptide/inhibitor complex or after the polypeptide is decomplexed from the tethered or modified compound of any of the formulae herein. Table 1 lists representative individual compounds of the invention and compounds employed in the compositions and methods of this invention.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term xe2x80x9cstablexe2x80x9d, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of excessive moisture for at least one week.
As used herein, the compounds of this invention, including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivative or prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The compounds of this invention may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. In general, the compounds of the formulae described herein are conveniently obtained via methods illustrated in General Synthetic Schemes I-IV and the Examples herein. These general schemes are also exemplified by the specific methods described in the Examples section below.
Thus, one embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein. Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the examples herein and then converting that intermediate(s) to a compound of the formulae described herein. Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein utilizing one or more of the chemical reactions described in the synthetic schemes or examples herein. Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein. 
In General Synthetic Scheme I, an appropriate benzaldehyde (S1) is converted to pyrimidinone S2 by reaction with an appropriate cyanoacetate (or equivalent) S-methylisothiouronium sulphate. Pyrimidinone S2 may be reacted with a substituted aniline or amine to form pyrimidinone S3.
In a similar fashion, as illustrated in General Synthetic Scheme II, a protected benzaldehyde (S4) may be reacted under the same conditions to provide pyrimidinone S5. Pyrimidinone S5 can be subsequently reacted with an aniline, amine or other appropriate heteroatom nucleophile to provide pyrimidinone S6. Subsequent deprotection (S7) and functionalization of the resultant heteroatom provides S8.
Alternatively, as shown in General Synthetic Scheme III, an appropriately substituted xcex2-ketoester (S9) can be condensed under similar conditions with S-methylisothiouronium sulphate to afford pyrimidinone S10. Nucleophilic addition to S10 then provides S11. Additionally, as illustrated in General Synthetic Scheme IV, an appropriately substituted xcex2-ketoester (S9) can be condensed with thiourea to afford S12. Subsequent sulfur alkylation and nucleophilic addition provides pryimidinone S13.
Thus, one embodiment relates to a method of making a compound of the formulae described herein, comprising 1) the step of reacting an aldehyde (or equivalent) with a cyanoacetate (or equivalent) and an alkylisothiouronium salt to form a pyrimidinone; 2) reacting said pyrimidinone with a nucleophilic agent (e.g., an aniline or amine) to form the compound of the formulae described herein. Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. Such agents may have carbon or a heteroatom (e.g, N, O, S) as the nucleophilic atom. In an alternate embodiment, the method of making a compound of the formulae described herein, comprises 1) preparation of a thio-substituted pyrimidone intermediate (as exemplified by S2, S5, S10 and S12 in the General Synthetic Schemes); and 2) reacting the pyrimidinone of step 1 with another chemical to form the compound of the formulae described herein. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after steps 1 and 2 described above, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser""s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The novel compounds of the present invention are excellent ligands for protein kinases, subsequences thereof, and homologous polypeptides. Accordingly, these compounds are capable of targeting and inhibiting kinase enzyme and subsequences thereof. Inhibition can be measured by various methods, including, for example, those methods illustrated in the examples below. The compounds described herein may be used in assays, including radiolabelled, antibody detection and fluorometric, for the isolation, identification, or structural or functional characterization of enzymes, peptides or polypeptides. Such assays include any assay wherein a nucleoside or nucleotide are cofactors or substrates of the peptide of interest, and particularly any assay involving phosphotransfer in which the substrates and or cofactors are ATP, GTP, Mg, Mn, peptides or polymeric amino acids.
Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise additional therapeutic agents, including, for example, immunosuppressants, anti-cancer agents, anti-viral agents, antiinflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproliferation compounds.
The term xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-xcex1-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as xcex1-, xcex2-, and xcex3-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-xcex2-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, alternatively between about 0.5 and about 75 mg/kg body weight per day of the kinase inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of kinase mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
When the compositions of this invention comprise a combination of a kinase inhibitor of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the kinase inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
According to one embodiment, the pharmaceutical compositions of this invention comprise an additional immunosuppression agent. Examples of additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
According to an alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise cytotoxic or hormonal anti-cancer agents or combinations thereof. Examples of anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, taxotere, colchicine, cyclosporin A, phenothiazines, interferons, thioxantheres, anti-estrogens (e.g., tamoxifen), aromatase inhibitors, anti-androgens, and LHRH antagonists.
According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an anti-viral agent. Examples of anti-viral agents include, but are not limited to, Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT, amprenavir and acyclovir.
Upon improvement of a patient""s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient""s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
In an alternate embodiment, this invention provides methods of treating, preventing, or relieving symptoms of disease in a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and combinations described above. Preferably, the mammal is a human. If the pharmaceutical composition only comprises the inhibitor of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an additional therapeutic agent, such as an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the inhibitor composition.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below: 
in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. The compounds may also occur in cis- or trans- or E- or Z-double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom (see below), whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). For example, a structure drawn as: 
is intended to encompass all of the following structures: 
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.